SUMMARY The overall goal of this project is to identify new therapies that target influenza virus replication. The global health burden of annual influenza infections and periodic epidemics coupled with the emergence of avian influenza viruses, like H5NX and H7N9, highlight the urgent need for new effective treatments. A primary concern with the current drugs used to treat influenza in the U.S. is the development of resistance mutations that negate therapeutic benefit. Both published evidence and clinical experience suggest strongly that targeting the influenza virus RNA dependent RNA polymerase (RdRp) complex is a rational approach for antiviral therapy. This complex is responsible for many viral functions, including 5 cap recognition, endonucleolytic cleavage, RNA synthesis, and polyadenylation providing multiple functional domains as targets for antiviral drug therapy and combination therapy. Agents can target the distinct functions and, theoretically, reduce the minimize development of resistance since resistance mutations would likely reduce the fidelity of the RdRp. One oral agent targeting the endonuclease domain, baloxavir, has shown efficacy in uncomplicated influenza and was recently approved in Japan for treating influenza in adults and children. A second oral agent targeting the 5 cap binding domain, pimodivir, has shown antiviral activity in uncomplicated influenza and is advancing in clinical development. A third oral agent, favipiravir, targeting the polymerase activity has been approved in Japan for treating novel influenza strains not inhibited by neuraminidase inhibitors. We have recently identified several potent molecules through a collaborative public private partnership that inhibit RdRp functions. This research team provides the medicinal chemistry expertise, follow up assays, and in vivo experience to transform active hits into lead compounds and promises to yield new classes of highly active molecules that target the RdRp complex.